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Space: Medicine's final frontier

This article was taken from the May 2011 issue of Wired magazine. Be the first to read Wired's articles in print before they're posted online, and get your hands on loads of additional content bysubscribing online.

On September 18, 2006, aboard the Space Shuttle Atlantis, astronaut Heidemarie Stefanyshyn-Piper turned a crank and gave millions of bacteria an impromptu bath. She was holding a carefully sealed device composed of several glass barrels, each containing separate fluids that could be mixed at will. Carefully, she dunked some dormant bacteria into a nutritious broth that allowed them to grow, change and multiply. At the same time, scientists under the supervision of Cheryl Nickerson turned a similar crank in a room at Kennedy Space Center in Orlando, Florida, designed to mimic the Shuttle's temperature and humidity. The scientists synchronised their efforts via real-time radio communication.

The co-ordinated experiment was a groundbreaking one: it demonstrated that bacteria turn into superbugs in the gravity-free environment of space, gathering together, gaining strength and becoming much more effective at causing disease.

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Science-fiction stories such as The Andromeda Strain love to play on the potential threat of alien infections, but earthly germs pose a far greater danger to human beings. With infectious powers bolstered by zero gravity, bacteria represent a significant risk to the health of space-faring humans, and it's a problem that an agency such as Nasa will have to crack if it is to send astronauts on longer missions. Nasa has been taking the problem seriously -- the Atlantis experiment was just part of a larger research programme in space bacteria. By observing how bacteria react to the extreme environment of space, its researchers hope to learn more about how they behave in the human body. "It gives us a new handle on how to develop new ways of treating, preventing or diagnosing infectious diseases," says Nickerson, a feisty 49-year-old professor at Arizona State University's Biodesign Institute who is at the heart of the research and specialises in infectious bacteria and how they cause diseases. In an animated, south-western lilt, she explains her simple yet ambitious goals. "The bugs are winning the war. We always have to stay a step ahead." She slaps her hand on the desk to stress the importance of every word. "It's unacceptable that infectious diseases are the leading cause of death in young adults and children worldwide. We can do better and will do better."

She wants nothing less than to find the next big weapons against infectious diseases.

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Cheryl Nickerson's interest in public health took a cosmological slant thanks to an old friendship. During her time as a PhD student at Louisiana State University, she met another student called Mark Ott. The two struck up a long-lasting alliance. Ott, who had a background in chemical engineering, taught Nickerson how to think mechanically and mathematically, while she taught him about genes and bacteria. From Louisiana, their paths separated. Ott took a position at Nasa's Johnson Space Center in Houston, Texas, where he monitors bacterial contamination in the air and water of the Shuttle and the International Space Station (ISS). Nickerson developed an interest in disease-causing bacteria, particularly salmonella, responsible for millions of cases of food poisoning, typhoid and other illnesses every year.

Their paths crossed during a phone conversation in May 1998, when Ott mentioned that space travel weakens astronauts' immune system. To Nickerson, this was only half the equation: no one knew whether infectious bacteria would change in space too. An astronaut's defences may be compromised, but what happens to their attackers?

From ballooning experiments in 1935, to the Sputnik satellites and Gemini spacecraft of the 50s and 60s, and on to the Mir, Apollo and Skylab programmes of the 80s and 90s, both Russia and the US have flown bacteria into space. Aboard these craft, bacteria were found to grow more quickly, become more resistant to antibiotics, and swap genes between one another more readily. But no one had tested their virulence -- the ability to cause disease. Nickerson saw the potential. "I asked Mark one of the more stupid questions I've ever asked," she says. "'Well, when can we fly an experiment in space?

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We have to test this! Can we fly right now?' He paused, took a deep breath and said, 'It doesn't quite work that way.'"

Ott began by introducing Nickerson to colleagues at Nasa. They included Duane Pierson, a microbiologist who was starting to consider the effects of space flight on bacteria. "We got Cheryl started on that about 12 years ago," he recalls, speaking from the Johnson Space Center in Houston. "She's our real success story.

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Nickerson started building a case for sending bacteria into space, by working out if they become more virulent in microgravity.

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On Earth, you cannot very well switch gravity off, but Nickerson and Ott did the next best thing -- they placed salmonella in special vats called rotating-wall vessels (RWVs). The rapidly spinning walls subject cells to conditions akin to freefall. The bacteria changed dramatically, becoming tougher to kill and more virulent. By 2002, Nickerson had the evidence she sought. She proved that there was a need for actual experiments in true microgravity.

So it was that, in September 2006, Stefanshyn-Piper submerged millions of Salmonella typhimurium into a nourishing liquid aboard the Atlantis. A day later, she turned a second handle and flooded the bacteria with a fixative, preserving their cells and genes for the journey home. Back on Earth, Nickerson compared these microbes to counterparts that had been treated the same way in gravity-normal Orlando.

The results were remarkable: the bacteria from the Shuttle had become more virulent. They killed half the infected mice at a third of the dose and in five fewer days than their Earthbound peers did.

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When Nickerson peeked at the cells under a microscope, she saw that they had not changed in size or shape. Instead, they had become better at forming biofilms -- the bacterial equivalent of cities.

In these communities, bacteria gather in large numbers, protected by a network of substances that they secrete.

The scale of these changes surprised Nasa experts. Neal Pellis, a senior scientist at Nasa's Space Life Sciences Directorate, says: "It's not something that you'd easily predict. Bacteria live in an environment where gravity has been constant for their entire existence and evolution." Pellis does not want to rule out the possibility that bacteria might have a gravity-sensing structure, but he thinks it is more likely that they are responding to other changes in their environment.

Cells in a flask experience very different forces when they leave the planet's atmosphere. In space, the convection currents that circulate the surrounding fluid vanish and the cells experience far less force from liquid passing over their surface, a quantity known as "fluid shear". Nickerson thinks these conditions mimic the spaces that bacteria are best adapted to: the guts, airways and urinary tract of their hosts. "Many of these conditions are relevant to what bacteria encounter on a daily basis in our bodies here on Earth," Nickerson says. When salmonella moves from the fast-flowing centre of the gut to the sheltered slow lanes of the bowel walls, fluid shear also falls. This changing force provides a signal that tells the bacteria to initiate their virulence programmes. Space travel simply tricks bacteria into responding as if they were in their hosts.

The result is a dramatic molecular makeover. When Nickerson analysed the genomes of her space-faring salmonella, she found that their disease-causing abilities were triggered by changes in the activity of 167 genes. Key to these changes is a protein called Hfq, a master switch that governs the network of active genes.

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Genes contain instructions for producing proteins and, when activated, these instructions are first transcribed into a related molecule called RNA. Hfq escorts these transcripts around the cell, influencing which of them will go on to produce proteins. It is both chaperone and overseer.

Nickerson found that Hfq becomes far less active in space-faring salmonella. As a result, some of the genes it controls are switched off while others are switched on, including those involved in forming biofilms and responding to harsh environments.

Nickerson confirmed the importance of Hfq by going back to the RWVs and lacing them with mutant salmonella that lacked this essential protein. Sure enough, the bacteria without Hfq never developed the hardiness and virulence common to normal ones.

Nickerson is very excited about Hfq, for it is not unique to salmonella: it lords over the genes of a wide variety of living things and has changed very little through the course of evolution.

Indeed, Nickerson will soon publish evidence that Hfq controls the virulence of two other infectious microbes in space -- Pseudomonas aeruginosa, a common bacterium that causes inflammation and blood poisoning, and Candida albicans, the fungus that causes thrush. "The evolutionarily conserved master switch gives us a target to look at," she says. Drugs or vaccines that hit Hfq could act as weapons against many infectious diseases.

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To Nickerson, these benefits are still a long way off -- "We're too early for a pill in a box," she says -- but Hfq is a valuable lead. First, Nickerson has to tease apart the ways in which the master switch controls a bacterium's transformation. In the meantime, Hfq's widespread effects could have immediate implications for astronauts' health: many microbes react to space flight in the same way that space-travelling humans will face souped-up versions of a wide range of infections. To make matters worse, bacteria could hardly have an easier time of finding new hosts than in the confines of a Shuttle or a space station. "The crew is in a closed environment," Nickerson says, "and there's no effective way of quarantining anything if there should be an infectious disease." Everyone is in very close contact. The same air and water circulates through the quarters. Mucus or cough droplets that would normally land can hang in the air indefinitely.

And many missions involve international crews, each bringing native microbes from their corner of the world.

Once bacteria find a new host, they also encounter weaker defences because space flight compromises the human immune system.

Our defence force -- white blood cells -- fails to activate properly against incoming threats. And those that do respond are ineffective shadows of themselves. "If you put that all together, it suggests that the risk is real and should be seriously considered when planning future extended space-flight missions," Nickerson says. Treating a sick astronaut is no easy matter, especially when flights contain neither doctors nor diagnostic equipment. "You've got astronauts up there going 28,000kph," Pierson says. "They call up a physician on the ground and they say, 'My tummy hurts.' You're going by symptoms, there's no laboratory confirmation at all." Antibiotics are the first line of defence, but against space-induced superbugs there is no guarantee they'll work. "Some bacteria exhibit increased antibiotic resistance in flight so extreme that you couldn't treat astronauts with levels of antibiotics that high,"

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This increased risk took its toll in many early space missions.

Around half of all Apollo astronauts took ill either during their flight or immediately upon return to Earth. During the fateful Apollo 13 mission, Fred Haise became feverish with a urinary infection triggered by P. aeruginosa, one of the stars of Nickerson's experiments. This bacterium tends to cause problems for people with weak immune systems. Astronauts fit the bill. "He was critically ill," Nickerson says. "Had Apollo 13 not gotten back when it did, even a day later, it could have been a very different outcome."

After the Apollo missions, Nasa created strict screening to prevent astronauts picking up infections. Surfaces are thoroughly cleaned and food checked closely. "We do an excruciating amount of monitoring of the crew environment," says Ott, who leads many of the checks. Despite intense cleaning, Ott found dirty globules of water floating in the Mir space station, harbouring fungi, bacteria, mites and parasites. Food products often contain bacteria such as salmonella and Staphylococcus aureus. "If we find something bad, we pull that lot," says Ott. "You think, 'Great, I've eliminated that possibility,' but you haven't, because you've only done random sampling."

The astronauts themselves have thorough check-ups, spending ten days in quarantine before flying. The procedures prevent fresh infections and spot any major threats, such as MRSA or tuberculosis. Bu they do nothing about the many microbes hidden in our bodies whose cells outnumber our own ten times over. Many of these passengers are benign and even necessary, but some cause disease when our defences falter. Staphylococcus aureus is one such bacterium, and according to Pierson it lurks in around 40 percent of crew members. "There are no sterile humans.

Wherever we go, they go," says Nickerson. She is studying these hitch-hikers to learn if space flight could unleash their darker side. Nor can medical screening pick up dormant infections lurking within our cells. Chickenpox, for example, is caused by Varicella zoster virus. Even after the spots have cleared, the viruses invade nerve cells and sit unnoticed for decades. "Every time they raise their head, the immune system bops 'em. If the immune system is down, there's no gatekeeper -- the virus pops out and causes shingles," says Pierson. Weakened immune systems are a hazard of space flight.

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Pierson has led the way on these discoveries. "Varicella is very rare in normal healthy people," he says, "but in astronauts, you'll find it in their saliva, all through the mission. This is an intact, infectious virus." The same applies to other viruses from the herpes family, which have a habit of becoming permanent stowaways. Compared to people on the ground, astronauts will shed ten times as much Epstein-Barr virus, a herpes virus that causes glandular fever, autoimmune diseases and some cancers.

It is no surprise then that, despite many safety measures and the peak physical condition of the crews, some fall sick. Over 106 Shuttle flights, there have been 29 recorded infections, whether viral, bacterial or fungal. Based on those statistics, crew members stand a one-in-25 chance of falling ill. Fortunately, the infections are usually minor and manageable. "As it stands, we don't have a recurrent problem with infections," Pellis says.

Indeed, in an assessment last year, Nasa concluded that flights of up to six months do not pose significant risks to astronauts.

Longer missions are a different story. Nasa still intends to launch trips to the Moon and Mars within the next decade, and that would change things dramatically. "It's a six-month trip to Mars and it's about that long back, too," says Pierson. "If you had an emergency on the way... [he pauses and chuckles]... it's going to be tough to manage, right? Those are our pretty big challenges."

The need for countermeasures is clear, and the search is well and truly on. Pierson says that anything that relieves stress could help, including exercise, decent sleep and even something as simple as chatting to friends and family. Some scientists are trying to reinforce the immune system using dietary supplements, testing everything from nucleotides -- the chemicals that make up DNA -- to compounds sourced from plants and fungi.

Meanwhile, Nickerson is looking for ways of controlling bacteria themselves. Hfq offers one possible route, and she has other promising leads. In March 2008, she sent more salmonella into space aboard the Space Shuttle Endeavour, repeating her Atlantis experiment to check that it wasn't a one-off. "We nailed it," she says. "Salmonella again was more virulent -- it was even hotter than the first time we flew it." But this time she managed to prevent that transformation by raising the levels of just five salts in the bacteria's broth. "We altered the ion levels and -- guess what! -- we completely shut down the virulence of salmonella."

Based on follow-up experiments with the RWVs, Nickerson thinks that phosphate is particularly important for keeping salmonella in check. For now, she does not know why, although previous studies have suggested that phosphate ions could affect the activity of Hfq. If phosphate ions are the cause, food supplements could be designed to ward off infections. Nickerson thinks it might be even easier to tweak the content of the astronauts' diets. "If you had a way of pre-treating your food with a different combination of ions, the virulence potential of any salmonella could be inactivated," she says.

Other insights are sure to follow. Her data on P. aeruginosa and C. albicans -- the other stars of her Atlantis experiments - will be published soon. She is developing more 3D facsimiles of human tissues to pit against bacteria for a more realistic look at the infection process. And last April she launched another experiment aboard the Space Shuttle Discovery, the first to pit human cells against salmonella in space.

That will be her fifth space experiment. "At the bench, every single day you're doing a new experiment to follow up on an observation you've made the day before. That's just not possible at the moment with space flight. We've been privileged to fly on Shuttle experiments, but there's been a one-to-two-year gap between each one. That makes it hard to advance your hypotheses as much as you would like."

The flights themselves are expensive and the crew have other priorities. On a two-week Shuttle flight, the crew has five minutes available for an experiment. Astronauts on the ISS are less constrained, but their time is still precious. The equipment lags behind standard lab technology, limited as it is in weight, bulk and power supply. Nickerson wants better. She is working with hardware designers to fit out the ISS with a more advanced generation of flight equipment.

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She is also stoking interest within the commercial space flight sector to make regular space experiments a reality. In October last year, she presented her research at the International Symposium for Personal and Commercial Space flight at New Mexico. Her pitch was simple: sending bacteria into space tells us more about how they behave on the ground, which will lead to new patentable strategies for fighting infectious disease. In the US alone, salmonella causes at least 1.4 million infections every year, leading to 15,000 hospitalisations and 580 deaths, soaking up around $3 billion.

That's one infection. "This is going to be bigger than salmonella," says Nickerson, "which is unveiling responses that will help us with other pathogens."

The talk went well. "I spoke to a lot of entrepreneurs who are very excited about using their capabilities to fund and fly research in space on a continuing basis," she says. She has confirmed interest from some big players. "You had people there like Robert Bigelow, Elon Musk, Sir Richard Branson...these are the players who are actually looking to advance this frontier."

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But not everyone sees the same potential. "I've been told that the research will produce absolutely no novel insight. I've been told that this is ludicrous, that this is a waste of time," she recalls with weariness but good humour. "If you make discoveries that are on the cutting edge, then you'd better be ready to hear that your work is heresy. I know we're doing darn good research.

Hearing no is just going to make me more determined."

Nickerson points out that many of the biggest discoveries in biology have come from putting living things in extreme environments. Kerry Mullis studied a bacterium that lives in hot undersea vents and found an enzyme that could create pieces of DNA at high temperatures. The enzyme was the basis of the polymerase chain reaction, a technique that revolutionised biology and earned Mullis a Nobel Prize. Barry Marshall showed that the bacterium Helicobacter pylori could thrive in the extreme acid of the stomach, and that it caused stomach ulcers. He too earned a Nobel Prize for his work. "Every time we push living systems to survive, respond and adapt to extreme environments, we acquire novel insight about these cells. And we've been able to take that knowledge and translate it into new drugs or technologies or products," Nickerson says. "I've had colleagues ask me why I would use the space flight to research infectious diseases. I think, 'Why in the world would you not have thought of doing that?' Space is the next logical extreme environment to look at."

This article was first published in the May 2011 issue of WIRED magazine